3,5,8-Trihydroxy-4-quinoline (THQ), isolated from a marine sponge, and a semi-synthetic derivative, 5,8-dimethoxy-e-hydroxy-4-quinolone (6), inhibited reverse transcriptase (RT) from HIV-1 and HIV-2, with IC50 values ranging from 2.4 to 43 muM. THQ interacted with a RT- DNA complex differently that other known RT inhibitors, suggesting this molecule inhibits RT via a novel mechanism. THQ and 6 thus represent important leads in the quest for non-nucleoside RT inhibitors for the treatment of AIDS. The goal of this Phase I project is to develop an efficient synthesis of 6, which possessed improved chemical stability relative to THQ. We will also synthesize a series of analogues representing regioisomers, isosteres and homologues with the intent of determining structural feature necessary for biological activity, as well as possibly identifying congeners having increased activity. The compounds will be evaluated for their ability to inhibit HIV-1- and HIV-2-mediated cytopathicity in vitro. The lead compound 6 and congeners possessing significant activity in the initial assay will also be evaluated for cytoprotection against a panel of viral mutants resistant to both nucleoside and non-nucleoside RT inhibitors, as well as for inhibition of HIV-1 and HIV-2 RT, and DNA polymerases alpha and beta. A future Phase II project will involve synthesis of a more extensive series of analogues, and determination of in vivo pharmacokinetic, toxicological and antiviral parameters using animal models.